1. Name Of The Medicinal Product
Aldactone 25mg
Aldactone 50mg
Aldactone 100 mg
2. Qualitative And Quantitative Composition
Each tablet contains 25mg, 50mg or 100mg spironolactone BP
3. Pharmaceutical Form
Aldactone 25mg tablets are buff, film coated tablets engraved “SEARLE 39” on one side.
Aldactone 50mg tablets are white, film coated tablets engraved “SEARLE 916” on one side.
Aldactone 100 mg tablets are buff, film coated tablets engraved “SEARLE 134” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
• Congestive cardiac failure
• Hepatic cirrhosis with ascites and oedema.
• Malignant ascites
• Nephrotic syndrome.
• Diagnosis and treatment of primary aldosteronism.
4.2 Posology And Method Of Administration
Administration of Aldactone once daily with a meal is recommended.
Adults
Congestive cardiac failure with oedema
For management of oedema an initial dose of 100mg/day Of spironolactone administered in either a single or divided doses is recommended, but may range from 25 to 200 mg daily. Maintenance dose should be individually determined.
Patients with severe heart failure (NYHA Class III-IV): Based on the Randomized Aldactone Evaluation Study (RALES; see also section 5.1), treatment in conjunction with standard therapy should be initiated at a dose of spironolactone 25 mg once daily if serum is potassium 4.4 Hyperkalemia in Patients with Severe Heart Failure for advice on monitoring serum potassium and serum creatinine.
Hepatic cirrhosis with ascites and oedema.
If urinary Na+/K+ ratio is greater than 1.0, 100mg/day. If the ratio is less than 1.0, 200-400mg/day. Maintenance dosage should be individually determined.
Malignant ascites
Initial dose usually 100-200mg/day. In severe cases the dosage may be gradually increased up to 400mg/day. When oedema is controlled, maintenance dosage should be individually determined.
Nephrotic syndrome
Usual dose 100-200mg/day. Spironolactone has not been shown to be anti-inflammatory, nor to affect the basic pathological process. Its use is only advised if glucocorticoids by themselves are insufficiently effective.
Diagnosis and treatment of primary aldosteronism.
Aldactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets.
Long test: Aldactone is administered at a daily dosage of 400mg for three to four weeks. Correction of hypokalaemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism.
Short test: Aldactone is administered at a daily dosage of 400mg for four days. If serum potassium increases during Aldactone administration but drops when Aldactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered.
After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, Aldactone may be administered at doses of 100mg-400mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Aldactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.
Elderly
It is recommended that treatment is started with the lowest dose and titrated upwards as required to achieve maximum benefit. Care should be taken with severe hepatic and renal impairment which may alter drug metabolism and excretion.
Children
Initial daily dosage should provide 3mg of spironolactone per kilogram body weight given in divided doses. Dosage should be adjusted on the basis of response and tolerance. If necessary a suspension may be prepared by crushing Aldactone tablets.
4.3 Contraindications
Aldactone is contraindicated in patients with anuria, acute renal insufficiency, rapidly deteriorating or severe impairment of renal function, hyperkalaemia, Addison's disease and in patients who are hypersensitive to spironolactone.
Aldactone should not be administered concurrently with other potassium conserving diuretics and potassium supplements should not be given routinely with Aldactone as hyperkalemia may be induced.
4.4 Special Warnings And Precautions For Use
Fluid and electrolyte balance: Fluid and electrolyte status should be regularly monitored particularly in the elderly, in those with significant renal and hepatic impairment
Hyperkalaemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities which may be fatal. Should hyperkalaemia develop Aldactone should be discontinued, and if necessary, active measures taken to reduce the serum potassium to normal.(See 4.3 Contraindications)
Hyponatremia may be induced, especially when Aldactone is administered in combination with other diuretics.
Reversible hyperchloraemic metabolic acidosis, usually in association with hyperkalaemia has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.
Concomitant use of aldactone with other potassium-sparing diuretics, ACE inhibitors, angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin, or potassium supplements, a diet rich in potassium, or salt substitutes containing potassium, may lead to severe hyperkalaemia.
Urea: Reversible increases in blood urea have been reported in association with Aldactone therapy, particularly in the presence of impaired renal function.
Hyperkalemia in Patients with Severe Heart Failure
Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving spironolactone. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L. The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of spironolactone, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL. (See section 4.2 Posology and method of administration; Severe heart failure).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Spironolactone has been reported to increase serum digoxin concentration and to interfere with certain serum digoxin assays. In patients receiving digoxin and spironolactone the digoxin response should be monitored by means other than serum digoxin concentrations, unless the digoxin assay used has been proven not to be affected by spironolactone therapy. If it proves necessary to adjust the dose of digoxin patients should be carefully monitored for evidence of enhanced or reduced digoxin effect.
Potentiation of the effect of antihypertensive drugs occurs and their dosage may need to be reduced when Aldactone is added to the treatment regime and then adjusted as necessary. Since ACE inhibitors decrease aldosterone production they should not routinely be used with Aldactone, particularly in patients with marked renal impairment.
As carbenoxolone may cause sodium retention and thus decrease the effectiveness of Aldactone concurrent use should be avoided.
Non-steroidal anti-inflammatory drugs may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins.
Spironolactone reduces vascular responsiveness to noradrenaline. Caution should be exercised in the management of patients subjected to regional or general anaesthesia while they are being treated with Aldactone.
In fluorimetric assays, spironolactone may interfere with the estimation of compounds with similar fluorescence characteristics.
Spironolactone has been shown to increase the half-life of digoxin.
Aspirin, indometacin, and mefanamic acid have been shown to attenuate the diuretic effect of spironolactone.
Spironolactone enhances the metabolism of antipyrine.
Spironolactone can interfere with assays for plasma digoxin concentrations
4.6 Pregnancy And Lactation
Pregnancy
Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses. The use of Aldactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and foetus.
Lactation
Metabolites of spironolactone have been detected in breast milk. If use of Aldactone is considered essential, an alternative method of infant feeding should be instituted.
4.7 Effects On Ability To Drive And Use Machines
Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.
4.8 Undesirable Effects
Gynaecomastia may develop in association with the use of spironolactone. Development appears to be related to both dosage level and duration of therapy and is normally reversible when the drug is discontinued. In rare instances some breast enlargement may persist.
The following adverse events have been reported in association with spironolactone therapy:
Body as a Whole: malaise
Endocrine Disorders: benign breast neoplasm, breast pain
Gastrointestinal Disorders: gastrointestinal disturbances, nausea
Hematologic Disorders: leukopenia (including agranulocytosis), thrombocytopenia
Liver Disorders: hepatic function abnormal
Metabolic and Nutritional Disorders: electrolyte disturbances, hyperkalemia
Musculoskeletal Disorders: leg cramps
Nervous System Disorders: dizziness
Psychiatric Disorders: changes in libido, confusion
Reproductive Disorders: menstrual disorders
Skin and Appendages: alopecia, hypertrichosis, pruritus, rash, urticaria,
Urinary System Disorders: acute renal failure
The following isolated adverse event has been reported in association with spironolactone therapy:
Skin & Appendages: Stevens Johnson Syndrome
4.9 Overdose
Acute overdosage may be manifested by drowsiness, mental confusion, nausea, vomiting, dizziness or diarrhoea. Hyponatraemia, or hyperkalaemia may be induced , but these effects are unlikely to be associated with acute overdosage. Symptoms of hyperkalaemia may manifest as paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia. Electrocardiographic changes are the earliest specific signs of potassium disturbances. No specific antidote has been identified. Improvement may be expected after withdrawal of the drug. General supportive measures including replacement of fluids and electrolytes may be indicated. For hyperkalaemia, reduce potassium intake, administer potassium-excreting diuretics, intravenous glucose with regular insulin or oral ion-exchange resins.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Spironolactone, as a competitive aldosterone antagonist, increases sodium excretion whilst reducing potassium loss at the distal renal tubule. It has a gradual and prolonged action.
Severe heart failure: The Randomized Aldactone Evaluation Study (RALES) was a multinational, double-blind study in 1663 patients with an ejection fraction of
5.2 Pharmacokinetic Properties
Spironolactone is well absorbed orally and is principally metabolised to active metabolites: sulphur containing metabolites (80%) and partly canrenone (20%). Although the plasma half life of spironolactone itself is short (1.3 hours) the half lives of the active metabolites are longer (ranging from 2.8 to 11.2 hours). Elimination of metabolites occurs primarily in the urine and secondarily through biliary excretion in the faeces.
Following the administration of 100 mg of spironolactone daily for 15 days in non-fasted healthy volunteers, time to peak plasma concentration (tmax), peak plasma concentration (Cmax), and elimination half-life (t1/2) for spironolactone is 2.6 hr., 80 ng/ml, and approximately 1.4 hr., respectively. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, tmax was 3.2 hr. and 4.3 hr., Cmax was 391 ng/ml and 181 ng/ml, and t1/2 was 13.8 hr. and 16.5 hr., respectively.
The renal action of a single dose of spironolactone reaches its peak after 7 hours, and activity persists for at least 24 hours
5.3 Preclinical Safety Data
Carcinogenicity : Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain. However the long term use of spironolactone in young patients requires careful consideration of the benefits and the potential hazard involved. Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses. The use of Aldactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and foetus.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Aldactone 25mg, 50mg & 100mg contain:
Calcium sulphate dihydrate, corn starch, polyvinyl pyrrolidone, magnesium stearate, felocofix peppermint, hypromellose, polyethylene glycol and opaspray yellow (contains E171 and E172).
6.2 Incompatibilities
None stated.
6.3 Shelf Life
The shelf life of Aldactone tablets is 5 years.
6.4 Special Precautions For Storage
Store in a dry place below 30oC.
6.5 Nature And Contents Of Container
Aldactone 25mg, 50mg & 100mg tablets may be packaged in the following containers:
Amber glass or plastic bottles containing 100 or 500 tablets.
HDPE containers of 50 or 1,000 tablets.
PVC/foil blister packs containing 100 or 500 tablets and PVC/foil blister calender pack of 28 tablets.
6.6 Special Precautions For Disposal And Other Handling
None
7. Marketing Authorisation Holder
Pharmacia Limited
Ramsgate Road
Sandwich
Kent, CT13 9NJ
United Kingdom
8. Marketing Authorisation Number(S)
Aldactone 25mg tablets: PL 00032/0394
Aldactone 50mg tablets: PL 00032/0395
Aldactone 100mg tablets: PL 00032/0393
9. Date Of First Authorisation/Renewal Of The Authorisation
Aldactone 25mg tablets: 10 February 2002
Aldactone 50mg tablets: 14 February 2002
Aldactone 100mg tablets: 7 February 2002
10. Date Of Revision Of The Text
08/2011
11. LEGAL STATUS
POM
Ref: AN4_2
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